Cancer Letters 328 (2013) 198–206

Contents lists available at SciVerse ScienceDirect

Cancer Letters

journal homepage: www.elsevier .com/ locate/canlet

Mini-review

Cancer genetics and genomics of human FOX family genes

Masuko Katoh a, Maki Igarashi b, Hirokazu Fukuda b, Hitoshi Nakagama b,c, Masaru Katoh c,⇑a M & M Medical BioInformatics, Tokyo 113-0033, Japanb Division of Cancer Development System, National Cancer Center, Tokyo 104-0045, Japanc Division of Integrative Omics and Bioinformatics, National Cancer Center, Tokyo 104-0045, Japan

a r t i c l e i n f o

Article history:Received 25 July 2012Received in revised form 20 September 2012Accepted 21 September 2012

Keywords:FOXPioneer factorNuclear hormone receptorGerm-line variationSomatic mutation

0304-3835/$ - see front matter � 2012 Elsevier Irelanhttp://dx.doi.org/10.1016/j.canlet.2012.09.017

⇑ Corresponding author. Address: Division of Integrics, National Cancer Center, 5-1-1 Tsukiji, Chuo Ward

E-mail address: mkatoh-kkr@umin.ac.jp (M. Katoh

a b s t r a c t

Forkhead-box (FOX) family proteins, involved in cell growth and differentiation as well as embryogenesisand longevity, are DNA-binding proteins regulating transcription and DNA repair. The focus of this reviewis on the mechanisms of FOX-related human carcinogenesis. FOXA1 is overexpressed as a result of geneamplification in lung cancer, esophageal cancer, ER-positive breast cancer and anaplastic thyroid cancerand is point-mutated in prostate cancer. FOXA1 overexpression in breast cancer and prostate cancer isassociated with good or poor prognosis, respectively. Single nucleotide polymorphism (SNP) within the50-UTR of the FOXE1 (TTF2) gene is associated with thyroid cancer risk. FOXF1 overexpression in breastcancer is associated with epithelial-to-mesenchymal transition (EMT). FOXM1 is overexpressed owingto gene amplification in basal-type breast cancer and diffuse large B-cell lymphoma (DLBCL), and it istranscriptionally upregulated owing to Hedgehog-GLI, hypoxia-HIF1a or YAP-TEAD signaling activation.FOXM1 overexpression leads to malignant phenotypes by directly upregulating CCNB1, AURKB, MYC andSKP2 and indirectly upregulating ZEB1 and ZEB2 via miR-200b downregulation. Tumor suppressor func-tions of FOXO transcription factors are lost in cancer cells as a result of chromosomal translocation, dele-tion, miRNA-mediated repression, AKT-mediated cytoplasmic sequestration or ubiquitination-mediatedproteasomal degradation. FOXP1 is upregulated as a result of gene fusion or amplification in DLBCLand MALT lymphoma and also repression of miRNAs, such as miR-1, miR-34a and miR-504. FOXP1 over-expression is associated with poor prognosis in DLBCL, gastric MALT lymphoma and hepatocellular car-cinoma but with good prognosis in breast cancer. In neuroblastoma, the entire coding region of the FOXR1(FOXN5) gene is fused to the MLL or the PAFAH1B gene owing to interstitial deletions. FOXR1 fusion genesfunction as oncogenes that repress transcription of FOXO target genes. Whole-genome sequencing datafrom tens of thousands of human cancers will uncover the mutational landscape of FOX family genesthemselves as well as FOX-binding sites, which will be ultimately applied for cancer diagnostics, prognos-tics, and therapeutics.

� 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Forkhead-box (FOX) proteins, regulating cell growth and differ-entiation as well as embryogenesis and longevity, have a conservedFOX domain and extra-FOX protein–protein interaction (PPI) do-mains or regions [1–5]. A FOX domain of approximately 100 aminoacids in length was originally identified as the conserved regionamong mammalian FOXA1 (HNF-3a), FOXA2 (HNF-3b), FOXA3(HNF-3c), and Drosophila Fork head [6,7]. The FOX domain is alsoknown as Winged-helix domain because its three-dimensionalstructure consists of two wing-like loops and three a-helices[8,9]. The FOX domain is involved in DNA binding [10,11], whileextra-FOX regions are involved in interaction with components

d Ltd. All rights reserved.

ative Omics and Bioinformat-, Tokyo 104-0045, Japan.).

of transcriptional activators, transcriptional repressors, or DNA re-pair complexes [12–14]. FOX family members are DNA-bindingproteins involved in transcriptional regulation as well as DNArepair.

Congenital disorders or hereditary diseases caused by FOXC1,FOXC2, FOXE1, FOXE3, FOXL2, FOXN1, FOXP2, and FOXP3 genes havepreviously been reviewed [1,2]. Germ-line FOXP2 point mutationsresult in a speech and language disorder of the verbal dyspraxiatype [15], whereas germ-line FOXP1 deletions occur in patientswith learning disabilities, developmental delays, and speech andlanguage disorders [16]. The FOXF1-MTHFSD-FOXC2-FOXL1 locusat human chromosome 16q24.1 is commonly deleted in neonatallylethal cases that have alveolar capillary dysplasia with misalign-ment of pulmonary veins (ACD/MPV), and frameshift or nonsensemutations of FOXF1 were identified as the cause of ACD/MPV[17]. Single nucleotide polymorphisms (SNPs) in the FOXA2, FOXJ1,FOXO3, and FOXP1 genes are associated with a fasting glycemic

Table 1Germ-line mutation or SNP of human FOX family genes associated with physiology or diseases.

Gene Chr. locus Germ-line mutations or variations Somatic mutations in human cancers

FOXA1 14q21.1 Amp (Lung, Esophageal, Breast, Thyroid)Mut (Prostate)

FOXA2 20p11.21 Fasting glycemic trait (SNP) Amp (Pancreas)FOXA3 19q13.32FOXB1 15q22.2FOXB2 9q21.2FOXC1 6p25.3 Axenfeld–Rieger syndromeFOXC2 16q24.1 Lymphedema–distichiasis syndromeFOXD1 5q12-q13FOXD2 1p33FOXD3 1p31.3 Amp (Breast)FOXD4 9p24.3FOXD4L1 2q13FOXD4L2 9p12FOXD4L3 9q21.11FOXD4L4 9q21.11FOXD4L5 9q21.11FOXD4L6 9q21.11FOXE1 9q22.33 Bamforth–Lazarus syndrome

Thyroid cancer (SNP)FOXE3 1p33 Anterior segment mesenchymal dysgenesisFOXF1 16q24.1 Alveolar capillary dysplasia with misalignment of pulmonary veins Del (Prostate)FOXF2 6p25.3FOXG1 14q12 Rett syndrome Amp (Hepatoblastoma)FOXH1 8q24.3FOXI1 5q35.1FOXI2 10q26.2FOXI3 2p11.2FOXJ1 17q25.1 Allergic rhinitis (SNP) Amp (Breast)FOXJ2 12p13.31FOXJ3 1p34.2FOXK1 7p22.1FOXK2 17q25.3FOXL1 16q24.1FOXL2 3q22.3 Blepharophimosis, ptosis, and epicanthus inversus syndrome Mut (Granulosa-cell tumor of ovary)FOXM1 12p13.33 Amp (Breast, DLBCL, B-CLL, MPNST)FOXN1 17q11.2 T-cell immunodeficiency, congenital alopecia, nail dystrophyFOXN2 2p16.3FOXN3 14q31.3-

q32.11FOXN4 12q24.11FOXO1 13q14.11 Type 2 diabetes (SNP) Transloc (Alveolar rhabdomyosarcoma)

Del (Prostate)FOXO2 1p34.2FOXO3 6q21 Premature ovarian failure Transloc (Secondary leukemia)

Longevity (SNP)FOXO4 Xq13.1 Transloc (ALL)FOXP1 3p13 Learning disability, developmental delay, speech and language

disorderAmp (DLBCL, MALT)

Generalized vitiligo (SNP) Transloc (DLBCL, MALT, B-ALL, Prostate)Del (Philadelphia-negative myeloproliferative neoplasm,Kidney)

FOXP2 7q31.1 Speech and language disorder (verbal dyspraxia)FOXP3 Xp11.23 Immunodysregulation, polyendocrinopathy, and enteropathy,

X-linkedMut & Del (Breast, Prostate)

FOXP4 6p21.1FOXQ1 6p25.3FOXR1 11q23.3 Del-fuse (Neuroblastoma)FOXR2 Xp11.21FOXS1 20q11.21

FOXC1, FOXF2 and FOXQ1 genes are clustered at human chromosome 6p25.3; FOXC2, FOXF1 and FOXL1 genes are clustered at 16q24.1; FOXD2 and FOXE3 genes are clustered at1p33; FOXJ3 and FOXO2 (FOXO6) genes are clustered at 1p34.2; FOXD4L3, FOXD4L4, FOXD4L5 and FOXD4L6 genes are clustered at 9q21.11. SNP: single nucleotide poly-morphism; Amp: gene amplification; Mut: point mutation; Transloc: translocation; Del: deletion; Del-fuse: interstitial deletion resulting in gene fusion; DLBCL: diffuse largeB-cell lymphoma; B-CLL: B-cell chronic lymphocytic leukemia; MPNST: malignant peripheral nerve sheath tumor; ALL: acute lymphoblastic leukemia; MALT: mucosa-associated lymphoid tissue lymphoma.

M. Katoh et al. / Cancer Letters 328 (2013) 198–206 199

trait, allergic rhinitis, longevity, and generalized vitiligo, respec-tively [18–21]. The haplotype of six SNPs in the FOXO1 gene is asso-ciated with a decreased risk of type 2 diabetes (T2DM) in theGerman population [22], whereas SNP rs2721068 in the FOXO1gene is associated with an increased risk of T2DM in German andFinnish populations [23]. Because FOX family members are in-volved in a variety of processes during embryogenesis and adult

tissue homeostasis, germ-line mutations or variations of FOX fam-ily members are often associated with human congenital disordersand diseases (Table 1).

Human cancers occur in a multi-step manner as a result of accu-mulation of epigenetic changes and genetic alterations [24–26].Somatic mutations of FOX family genes in various types of humancancers have been reviewed previously [3–5,27–29]. Currently,

200 M. Katoh et al. / Cancer Letters 328 (2013) 198–206

novel data on somatic mutations of FOX family members are accu-mulating in the public database owing to the advancement andspread of the exome or whole-genome sequencing technologies.Point mutations, gene amplifications, and translocations of FOXfamily genes in tumor cells directly alter the functions of FOX fam-ily members, whereas aberrant activation of cancer-associated sig-naling cascades involved in transcriptional regulation leads to thedysregulated expression of FOX family members. Here, the geneticalterations and dysregulated expression of FOX family genes are re-viewed, with a focus on the mechanisms of human carcinogenesis.

2. FOXA1

The FOXA1 gene at human chromosome 14q21.1 is amplified inlung cancer, esophageal cancer [30], estrogen receptor (ER)-positivebreast cancer [31], anaplastic thyroid cancer [32], and metastaticprostate cancer [33]. In addition to gene amplifications, FOXA1 pointmutations also occur in prostate cancer [34].

FOXA1 is overexpressed in some cases of lung cancer, esopha-geal cancer, breast cancer, and thyroid cancer as a result of geneamplification [30–32]. However, gene amplification of FOXA1 is rel-atively rare in primary breast cancers [35]. Because FOXA1 is a di-rect target gene of estrogen-ER signaling [36], FOXA1 isupregulated in most cases of ER-positive breast cancer as a resultof ER-dependent transcriptional regulation [37]. FOXA1 is also pref-erentially upregulated in androgen-receptor (AR)-dependent pros-tate cancer [38].

FOXA1 is the representative member of the FOXA subfamily,consisting of an N-terminal transactivation domain, a central FOXdomain, and a C-terminal histone-binding transactivation domain[39]. The FOX domain and the C-terminal domain of FOXA1 are in-volved in its association with double-strand genomic DNA and his-tone H3/H4, respectively. FOXA1 binds to the Forkhead-binding

Compact chromatin

Open chromatin

Cell lineage - or tumor type - specific transcription

FOXA

FOXAT F

Fig. 1. The context-dependent transcriptional program of FOXA1. FOXA1 is apioneer factor that opens up compact chromatin. Other transcription factors, suchas estrogen receptor (ER), androgen receptor (AR) and glucocorticoid receptor (GR),subsequently bind to the FOXA1-dependent open chromatin regions, whichactivates cell lineage- or tumor type-specific transcriptional programs. FOXA1overexpression is associated with good prognosis in breast cancer but with poorprognosis in prostate cancer.

motif within highly compacted chromatin regions and then in-duces the relaxation of FOXA1-bound loci through the replacementof linker histone H1, the dimethylation of histone H3 lysine 4(H3K4me2), and the demethylation of genomic DNA [10,40–43].FOXA1 with chromatin opening potential is a ‘‘pioneer factor’’[44,45] that releases the safety catch for other transcription factorsto trigger transcriptional programs (Fig. 1).

FOXA1 and ER are required for transcription of TFF1, RPS6KL1,and ABCC5 in estrogen-dependent breast cancer cells [36]. FOXA1and AR are required for transcription of PSA in androgen-dependent prostate cancer cells [46], while FOXA1 and MYBL2/CREB1 are required for transcription of CCNE2 and E2F1 incastration-resistant prostate cancer cells [47]. FOXA1 pointmutations result in repression of AR-dependent transcription andincreased proliferation of prostate cancer cells [34]. FOXA1 upreg-ulation is associated with good prognosis in breast cancer patientsowing to its preferential upregulation in the ER-positive subtype[48], whereas FOXA1 upregulation is associated with poorprognosis in prostate cancer patients [49]. Upregulation or highexpression levels of FOXA1 is associated with prognosis of cancerpatients in a context-dependent manner that depends on theexistence of FOXA1 cofactors involved in cell lineage- or tumortype-specific transcriptional programs and FOXA1 point mutationsaltering the transcriptional landscape.

3. FOXM1

The FOXM1 gene at human chromosome 12p13.33 is amplifiedin 5.6% of breast cancers [35], 42% of non-Hodgkin’s lymphomas[50], and 58% of malignant peripheral nerve sheath tumors [51].Amplification of the FOXM1 gene is enriched in basal-type breastcancers, whereas amplification of FOXM1 gene is commonly ob-served in three major subtypes of non-Hodgkin’s lymphoma: dif-fuse large B-cell lymphoma (DLBCL), follicular lymphoma, and B-cell chronic lymphocytic leukemia (CLL).

FOXM1 mRNA is upregulated in basal-type breast cancer [35],non-Hodgkin’s lymphoma [50], and malignant peripheral nervesheath tumors [51] as a result of gene amplification of FOXM1 it-self. Because Hedgehog signaling to GLI [52,53], hypoxia signalingto HIF-1a [54], and the YAP-TEAD transcriptional complex [55] areall involved in FOXM1 transcription, FOXM1 mRNA is also upregu-lated in basal cell carcinoma [52], pancreatic cancer [56], cervicalcancer [57], head and neck squamous cell carcinoma (SCC) [58],lung cancer [59], hepatocellular carcinoma (HCC) [60], medullo-blastoma [61], malignant mesothelioma [55], and bladder cancer[62].

FOXM1 protein, consisting of FOX domain and transactivationdomain, is phosphorylated by ERK on Ser331 and Ser704 in thePro-Gly-Ser-Pro (PGSP) motif. Unphosphorylated FOXM1 is locatedin the cytoplasm, whereas phosphorylated FOXM1 is located in thenucleus [63]. Aberrant activation of receptor tyrosine kinases(RTKs), RAS, RAF, or MAPK2 in tumor cells leads to ERK-mediatedphosphorylation and nuclear accumulation of FOXM1, which pro-motes the FOXM1-dependent transcriptional program. FOXM1 isfunctionally activated in tumor cells as a result of transcriptionalupregulation of FOXM1 mRNA as well as ERK-mediated phosphor-ylation of FOXM1 protein (Fig. 2).

Overexpression of FOXM1 leads to direct upregulation ofCDC25B, CCNB1 (Cyclin B1), AURKB (Aurora kinase B), PLK1 (Polo-likekinase 1), CENPA, CENPB, MYC (c-Myc), SKP2, MMP2, and VEGF[64–67] as well as indirect upregulation of ZEB1 and ZEB2 throughmicroRNA-200b (miR-200b) downregulation [68]. The SKP2 geneencodes a component of the ubiquitin ligase involved in theproteasome-mediated degradation of CDKN1A (p21, CIP1, orWAF1), CDKN1B (p27, or KIP1), FOXO1, DUSP1, and SMAD4 [69].

FAT

RTK

FOXM1 gene

FOXM1

FOXM1P

FOXM1 - target genes

CDC25B, CCNB1, AURKB, PLK1,

CENPA, CENPB, MYC, KP2, etc

RAS

RAF

MAP2K

ERK

Malignant phenotypes

Growth factorHedgehog

PatchedSmoothened

Hypoxia

GLIHIF1αα

TEAD

YAP

Fig. 2. FOXM1 upregulation results in malignant phenotypes. FOXM1 is transcriptionally upregulated by the Hedgehog-GLI, the hypoxia-HIF1a, and the YAP-TEAD signalingcascades. In addition, FOXM1 mRNA is overexpressed owing to gene amplification in basal-type breast cancer, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma,and B-cell chronic lymphocytic leukemia (CLL). The aberrant activation of receptor tyrosine kinase (RTK)-RAS-RAF signaling cascade leads to ERK-mediated FOXM1phosphorylation, which results in transcriptional upregulation of FOXM1 target genes, such as CDC25B, CCNB1, AURKB, PLK1, CENPA, CENPB, MYC, and SKP2. Because FOXM1induces malignant phenotypes, FOXM1 overexpression is associated with poor prognosis in lung cancer, medulloblastoma, breast cancer, gastric cancer, and pancreaticcancer.

M. Katoh et al. / Cancer Letters 328 (2013) 198–206 201

Upregulation of CDC25B, cyclin B1, AURKB, PLK1, CENPA, CENPBand MYC and the downregulation of p27KIP1 and p21WAF1 areinvolved in cell-cycle progression. MMP2 and VEGF are involvedin invasion and angiogenesis, respectively. ZEB1 and ZEB2 areinvolved in epithelial-to-mesenchymal transition (EMT). BecauseFOXM1 induces malignant phenotypes (Fig. 2), FOXM1 proteinupregulation is associated with poor prognosis for various typesof human cancers, including lung cancer, medulloblastoma, breastcancer, gastric cancer, and pancreatic cancer [59,61,66,70].

4. FOXO subfamily genes

The FOXO1, FOXO2 (FOXO6), FOXO3, and FOXO4 genes are FOXOsubfamily members [3]. The RXRSCTWPL motif in the N-terminalregion and the FOX domain containing a RRRAXSMD motif are con-served in all members of the FOXO subfamily, while theRXRXXSNASXXSXRLSP motif in the middle region is conserved inthe FOXO1, FOXO3, and FOXO4 proteins. In the nucleus, FOXOsbind to their consensus DNA-binding motif to activate transcrip-tion of their target genes, such as CDKN1A, CDKN1B, GADD45,SOD2 (manganese superoxide dismutase), FASLG (Fas ligand),TRAIL, and BIM (BCL2-like 11) [12,71,29]. CDKN1A and CDKN1Bare cyclin-dependent kinase inhibitors involved in cell cycle arrestat the G1 phase. GADD45 and SOD2 are involved in DNA repair andstress response, respectively. Fas ligand, TRAIL and BIM are in-volved in apoptosis. FOXO transcription factors can function as tu-mor suppressors.

The FOXO1 gene at human chromosome 13q14.11 is fused toeither the PAX3 or the PAX7 gene as a result of chromosomal trans-location in alveolar rhabdomyosarcoma. The FOXO3 gene at 6q21

and the FOXO4 gene at Xq13.1 are fused to the MLL gene as a resultof chromosomal translocation in secondary leukemia and acutelymphoblastic leukemia (ALL), respectively [29]. The FOXO1 geneis located within the commonly deleted region in prostate cancer,and the FOXO1 mRNA level is frequently downregulated in prostatecancer [72]. The FOXO1 gene is a direct target of the EWS-FLI1 fu-sion repressor, and FOXO1 mRNA is downregulated in Ewing’s sar-coma cells [73]. FOXO4 mRNA, one of the targets of miR-499-5p, isdownregulated in some cases of colorectal cancer that have miR-499-5p upregulation [74].

The FOXO proteins consist of FOX domain and transactivationdomain. The function of FOXO proteins is regulated by posttransla-tional modifications, such as phosphorylation, acetylation, andubiquitination [75,76]. AKT phosphorylates FOXO1, FOXO3, andFOXO4 on Ser/Thr residues in three RXRXXS/T motifs, and caseinkinase 1 (CK1) subsequently phosphorylates the Ser residues inSXXS sequence neighboring the third RXRXXS/T motif. Primingphosphorylation by AKT combined with subsequent phosphoryla-tion by CK1 leads to sequestration of FOXOs in the cytoplasm,which abrogates their transcriptional functions in the nucleus[77,78]. FOXO transcriptional activity is also inhibited owing tophosphorylation by IKKb, ERK1/2, DYRK1, CDK2, and NLK, as wellas acetylation by CBP, p300, and PCAF [76,79]. Growth factors, suchas insulin, IGF1, EGF, and FGF, bind to ligand-specific RTKs to acti-vate the PI3K-AKT signaling cascade, whereas PTEN inhibits thePI3K-AKT signaling cascade. Aberrant PI3K-AKT signaling activa-tion based on gain-of-function mutations of RTKs or PI3K compo-nents or loss-of-function mutations of PTEN leads to functionalloss of FOXO transcription factors due to cytoplasmicsequestration.

202 M. Katoh et al. / Cancer Letters 328 (2013) 198–206

SKP2 is an E3 ubiquitin ligase for FOXO1 [69], while MDM2 is anE3 ubiquitin ligase for FOXO1, FOXO3, and FOXO4 [80,81]. Becausepoly-ubiquitinated FOXO proteins are degraded by the protea-some, SKP2 and MDM2 are involved in degradation of FOXO tran-scription factors. MDM2, which is induced by p53, is also involvedin the degradation of p53 by the proteasome. Gene amplificationand overexpression of MDM2 in breast cancer, glioblastoma, oste-osarcoma, and liposarcoma [82] leads to functional loss of p53and FOXO proteins due to proteasome degradation.

The tumor suppressor functions of FOXO transcription factorsare lost in cancer cells as a result of chromosomal translocationsor deletions of FOXO genes, miRNA-mediated repression of FOXOmRNAs, AKT-mediated cytoplasmic sequestration of FOXO pro-teins, or ubiquitination-mediated proteasomal degradation ofFOXO proteins.

5. FOXP1

The FOXP1 gene at human chromosome 3p13 is fused to theimmunoglobulin heavy chain (IGH) locus as a result of chromo-somal translocations in DLBCL and mucosa-associated lymphoidtissue (MALT) lymphoma [27,83]. FOXP1 is fused to either thePAX5 or the ABL1 gene in B-ALL [84,85], and is fused to the ETV1gene in prostate cancer [86]. The FOXP1 gene is amplified in DLBCLand MALT lymphoma either with or without translocation [87]. Bycontrast, the FOXP1 gene is deleted in Philadelphia chromosome-negative myeloproliferative neoplasms [88] and clear cell-typekidney cancer [89].

FOXP1 mRNA is upregulated in MALT lymphoma with FOXP1translocation [83], non-MALT gastric cancer [90], and oral SCC withrepressed miR-504 [91]. FOXP1 protein is upregulated in DLBCLand MALT lymphoma with FOXP1 translocation [87] or repressedmiR-34a [92] and is also upregulated in HCC with repressed miR-1 [93]. FOXP1 mRNA is downregulated in kidney cancer [89], andcolon cancer [90]. FOXP1 expression is induced by translocation,gene amplification, and estrogen-ER signaling and is repressed bymiR-1, miR-34a, and miR-504.

The FOXP1 transcription factor consists of a poly-Gln region, aC2H2-type zinc finger domain, a leucine zipper domain, and aFOX domain [90]. Rodent Foxp1 represses the transcription ofSox17 and Nkx2.5 in developing cardiomyocytes [94] and activatesthe transcription of Rag1 and Rag2 in developing B cells [95]. Theability of FOXP1 to repress or activate the transcription of targetgenes depends on either the cellular lineage or the binding partner.

FOXP1 functions as a cancer driver in some tumors but as a tu-mor suppressor in others [96]. Wild-type FOXP1 acts like a tumorsuppressor gene in many tissues or organs, while shorter isoformsof FOXP1 act like oncogenes in DLBCL and MALT [27]. In addition tocell lineage- or tumor type-specific transcriptional program, exis-tence of shorter isoforms affects the behavior of FOXP1 during car-cinogenesis. FOXP1 is therefore associated with the prognosis ofcancer patients in a context-dependent manner. For example, theprognosis of FOXP1-positive DLBCL [97], gastric MALT lymphoma[98], and HCC [99] is poor, but the prognosis of FOXP1-positivebreast cancer is good [100].

6. FOXR1

FOXR1, also known as FOXN5, was initially identified and char-acterized as a cancer-associated gene located at human chromo-some 11q23.3, which is frequently deleted in neuroblastoma[101]. In neuroblastoma, FOXR1 is fused to the MLL or the PAFAH1Bgene owing to interstitial deletions which results in the overex-pression of fusion transcripts containing the entire coding regionof FOXR1 [102]. FOXR1 silencing in HOS osteosarcoma cells leads

to the upregulation of FOXO target genes, such as CDKN1A andCDKN1B, and the inhibition of cellular proliferation. The overex-pression of FOXR1 in JoMa1 neuroblasts that have an inducibleER-MYC transgene promotes cellular proliferation even in the ab-sence of MYC induction [102]. Taken together, these findings indi-cate that FOXR1 fusion genes function as oncogenes that repressthe transcription of FOXO target genes.

7. Other FOX genes

FOXC2 expression is regulated by a network of Hedgehog andTGFb signaling cascades [53,103]. Because FOXC2 is involved inEMT [103] and angiogenesis [104], FOXC2 expression is associatedwith the poor prognosis of basal-type breast cancers that co-ex-press GLI1 [105] and esophageal SCC [106].

FOXE1 functions as a pioneer factor that opens up compactchromatin to promote thyroid hormone-induced transcriptionalregulation [107]. The rs1867277 SNP within the 50-UTR of theFOXE1 gene, which creates a binding site for USF1 and USF2, isassociated with susceptibility to thyroid cancer [108]. FOXE1 is re-pressed in cutaneous SCC as a result of promoter hypermethylation[109] but is upregulated in basal cell carcinoma as a result ofHedgehog-GLI signaling activation [110].

The FOXF1 locus at human chromosome 16q24.1 is deleted inprostate cancer, and FOXF1 mRNA expression is downregulated insome cases of prostate cancer [111]. Copy number aberrationsand expression levels of FOXC2 and FOXL1, which neighbor FOXF1,should be investigated to determine which FOX gene is truly in-volved in prostate cancer. Expression of FOXF1 mRNA is also down-regulated in some cases of breast cancer and colorectal cancer[112,113]. FOXF1 downregulation in breast cancer cells is due toepigenetic silencing, and re-expression of FOXF1 using pharmaco-logic unmasking is associated with cell cycle arrest at the G1 phase[112]. Overexpression of FOXF1 is associated with a mesenchymalphenotype and an increased invasion potential in breast cancer[114]. FOXF1 upregulation leads to EMT manifested by mesenchy-mal phenotype and G1 arrest in breast cancer.

FOXQ1 is upregulated by TGFb signaling and is also involved inEMT [115,116]. Because FOXQ1 is expressed in basal-type breastcancers with a higher grade, the prognosis of FOXQ1-positivebreast cancer is poor [117].

Gene amplification of FOXA2 in pancreatic cancer [118], FOXD3and FOXJ1 in breast cancer [35], and FOXG1 in hepatoblastoma[119] has been reported. Point mutations of FOXL2 in granulosa-cell ovary tumors [120] as well as point mutations and deletionsof FOXP3 in breast and prostate cancer [121,122] have also beenreported.

8. Conclusion

FOX family genes are involved in carcinogenesis as oncogenesand/or tumor suppressor genes. Germ-line variation of FOXE1 leadsto a genetic predisposition to thyroid cancer. Epigenetic changes ofFOX family genes as well as genetic alterations of FOX family genes,such as copy number aberration, translocation and point mutation,occur in various types of human cancers (Table 1). Overexpressionof FOXA1 or FOXP1 is associated with good or poor prognosisdepending on the tumor type, whereas overexpression of FOXM1is associated with poor prognosis.

9. Perspectives

Foxa1 and Foxa2 are redundantly involved in progression ofhepatocarcinogenesis through induction of the AR-target genes inmale mice, whereas Foxa1 and Foxa2 are redundantly involved in

1st - generation Sequencing(Sanger)

2nd - generation Sequencing(454 Life Science, Illumina)

3rd - generation Sequencing(Pacific Biosciences)

Mutation landscape of

FOX family genes and

FOX-binding sites

in human cancers

Cancer diagnostics, prognostics & therapeutics

Fig. 3. Whole-genome sequencing in the era of personalized medicine.

M. Katoh et al. / Cancer Letters 328 (2013) 198–206 203

suppression of hepatocarcinogenesis through induction of the ER-target genes in female mice [123]. In addition, point mutations orSNPs at the FOXA2-binding sites within the regulatory regions ofPPM1L, FGL1, BTG1, and ABCC4 genes preferentially occur in humanfemale HCC samples, which results in decreased binding of FOXA2and ER [123]. These results point out the following major issues tobe further addressed in the FOX field: (i) context-dependency ofFOX functions during carcinogenesis; and (ii) genomics and genet-ics focusing on the FOX-binding sites.

FOXA1 and FOXP1 are bi-functional cancer-associated genes,which are oncogenic or tumor suppressive in a context-dependentmanner as mentioned above. In contrast, other classes of cancer-associated genes are consistently oncogenic or tumor suppressive:MYC, MYCN and GLI1 genes, encoding transcription factors involvedin cell-cycle progression and anti-apoptosis, are oncogenic[53,124,125]; TP53 and RB genes, encoding transcription factors in-volved in cell-cycle arrest and apoptosis, are tumor suppressive[126,127]. FOXA1 is a pioneer factor to open up chromatin for tis-sue-specific transcription factors, such as ER and AR. FOXA1 is in-volved in the transcriptional regulation of target genes of tumor-type specific transcription factors that bind to the neighboring re-gions of FOXA1-binding sites. Because it is hypothesized thatFOXA1 functions as a pioneer factor due to the structural similaritybetween the FOX domain and histon, there is a possibility thatother FOX family members also function as pioneer factors. FOXM1and FOXOs are preferentially oncogenic and tumor suppressive,respectively; however, these FOXs might also be bi-functional can-cer-associated genes. Therefore, oncogenic as well as tumor sup-pressive functions of all FOX family members should becomprehensively investigated in various types of human cancers.

FOX-targeted therapeutics is also a hot issue. High-throughputcell-based assay is utilized for the screening of small-moleculecompounds targeted to the oncogenic FOX family members. Sio-mycin A and thiostrepton inhibit growth of tumor cells withFOXM1 activation through downregulation of FOXM1 expressionand transcriptional repression of FOXM1-target genes [128,129].Docking simulation software is applicable for in silico screeningof small-molecule compounds directly binding to the FOX domainof FOXA1 protein using its three-dimensional structure. However,small-molecule compounds targeted FOXA1 might not be suitablefor clinical application owing to the context-dependent functionsof the FOXA1 as mentioned above. Because small-molecule inhibi-tors of ER and AR are in the clinical use for breast cancer and pros-tate cancer, respectively, it would be more appropriate andreasonable to target tissue-specific transcription factorsco-operating with the FOXA1 pioneer factor.

Recent innovations in both sequencing and information tech-nologies [130] have drastically changed modern science, especially

cancer research. Whole-genome sequencing data from tens ofthousands of human cancers will reveal the mutational landscapeof FOX family genes themselves as well as FOX-binding sites withinthe regulatory regions of FOX-target genes, which could promoteunderstanding of the mechanisms of FOX-related carcinogenesisand development of novel cancer diagnostics, prognostics andtherapeutics (Fig. 3).

Acknowledgements

This study was supported in part by Grants-in-aids for the 3rdTerm Comprehensive 10-Year Strategy for Cancer Control fromthe Ministry of Health, Labour and Welfare of Japan, and theNational Cancer Center Research and Development Fund.

References

[1] P. Carlsson, M. Mahlapuu, Forkhead transcription factors: key players indevelopment and metabolism, Dev. Biol. 250 (2002) 1–23.

[2] O.J. Lehmann, J.C. Sowden, P. Carlsson, T. Jordan, S.S. Bhattacharya, Fox’s indevelopment and disease, Trends Genet. 19 (2003) 339–344.

[3] M. Katoh, M. Katoh, Human FOX gene family, Int. J. Oncol. 25 (2004) 1495–1500.

[4] S. Hannenhalli, K.H. Kaestner, The evolution of Fox genes and their role indevelopment and disease, Nat. Rev. Genet. 10 (2009) 233–240.

[5] B.A. Benayoun, S. Caburet, R.A. Veitia, Forkhead transcription factors: keyplayers in health and disease, Trends Genet. 27 (2011) 224–232.

[6] D. Weigel, G. Jürgens, F. Küttner, E. Seifert, H. Jäckle, The homeotic gene forkhead encodes a nuclear protein and is expressed in the terminal regions of theDrosophila embryo, Cell 57 (1989) 645–658.

[7] E. Lai, K.L. Clark, S.K. Burley, J.E. Darnell Jr., Hepatocyte nuclear factor 3/forkhead or ‘‘winged helix’’ proteins: a family of transcription factors of diversebiologic function, Proc. Natl. Acad. Sci. USA 90 (1993) 10421–10423.

[8] K.L. Clark, E.D. Halay, E. Lai, S.K. Burley, Co-crystal structure of the HNF-3/forkhead DNA-recognition motif resembles histone H5, Nature 364 (1993) 412–420.

[9] M.J. van Dongen, A. Cederberg, P. Carlsson, S. Enerback, M. Wikstrom, Solutionstructure and dynamics of the DNA-binding domain of the adipocyte-transcription factor FREAC-11, J. Mol. Biol. 296 (2000) 351–359.

[10] S. Pierrou, M. Hellqvist, L. Samuelsson, S. Enerbäck, P. Carlsson, Cloning andcharacterization of seven human forkhead proteins: binding site specificityand DNA bending, EMBO J. 13 (1994) 5002–5012.

[11] Y. Fujii, M. Nakamura, FOXK2 transcription factor is a novel G/T-mismatchDNA binding protein, J. Biochem. 147 (2010) 705–709.

[12] M. Almeida, L. Han, M. Martin-Millan, C.A. O’Brien, S.C. Manolagas, Oxidativestress antagonizes Wnt signaling in osteoblast precursors by diverting b-catenin from TCF- to FoxO-mediated transcription, J. Biol. Chem. 282 (2007)27298–27305.

[13] A. Roesch, A.M. Mueller, T. Stempfl, C. Moehle, M. Landthaler, T. Vogt, RBP2-H1/JARID1B is a transcriptional regulator with a tumor suppressive potentialin melanoma cells, Int. J. Cancer 122 (2008) 1047–1057.

[14] A.B. Brenkman, N.J. van den Broek, P.L. de Keizer, D.C. van Gent, B.M.Burgering, The DNA damage repair protein Ku70 interacts with FOXO4 tocoordinate a conserved cellular stress response, FASEB J. 24 (2010) 4271–4280.

[15] S.E. Fisher, C. Scharff, FOXP2 as a molecular window into speech andlanguage, Trends Genet. 25 (2009) 166–177.

204 M. Katoh et al. / Cancer Letters 328 (2013) 198–206

[16] D.F. Newbury, A.P. Monaco, Genetic advances in the study of speech andlanguage disorders, Neuron 68 (2010) 309–320.

[17] P. Stankiewicz, P. Sen, S.S. Bhatt, M. Storer, Z. Xia, B.A. Bejjani, Z. Ou, J.Wiszniewska, D.J. Driscoll, M.K. Maisenbacher, J. Bolivar, M. Bauer, et al.,Genomic and genic deletions of the FOX gene cluster on 16q24.1 andinactivating mutations of FOXF1 cause alveolar capillary dysplasia and othermalformations, Am. J. Hum. Genet. 84 (2009) 780–791.

[18] A.K. Manning, M.F. Hivert, R.A. Scott, J.L. Grimsby, N. Bouatia-Naji, H. Chen, D.Rybin, C.T. Liu, L.F. Bielak, I. Prokopenko, N. Amin, D. Barnes, et al., A genome-wide approach accounting for body mass index identifies genetic variantsinfluencing fasting glycemic traits and insulin resistance, Nat. Genet. 44(2012) 659–669.

[19] C.S. Li, S.C. Chae, J.H. Lee, Q. Zhang, H.T. Chung, Identification of singlenucleotide polymorphisms in FOXJ1 and their association with allergicrhinitis, J. Hum. Genet. 51 (2006) 292–297.

[20] B.J. Willcox, T.A. Donlon, Q. He, R. Chen, J.S. Grove, K. Yano, K.H. Masaki, D.C.Willcox, B. Rodriguez, J.D. Curb, FOXO3A genotype is strongly associated withhuman longevity, Proc. Natl. Acad. Sci. USA 105 (2008) 13987–13992.

[21] Y. Jin, S.A. Birlea, P.R. Fain, C.M. Mailloux, S.L. Riccardi, K. Gowan, P.J. Holland,D.C. Bennett, M.R. Wallace, W.T. McCormack, E.H. Kemp, D.J. Gawkrodger,et al., Common variants in FOXP1 are associated with generalized vitiligo, Nat.Genet. 42 (2010) 576–578.

[22] Y. Böttcher, A. Tönjes, B. Enigk, G.H. Scholz, M. Blüher, M. Stumvoll, P. Kovacs,A SNP haplotype of the forkhead transcription factor FOXO1A gene may have aprotective effect against type 2 diabetes in German Caucasians, DiabetesMetab. 33 (2007) 277–283.

[23] K. Müssig, H. Staiger, F. Machicao, A. Stancáková, J. Kuusisto, M. Laakso, C.Thamer, J. Machann, F. Schick, C.D. Claussen, N. Stefan, A. Fritsche, et al.,Association of common genetic variation in the FOXO1 gene with b-celldysfunction, impaired glucose tolerance, and type 2 diabetes, J. Clin.Endocrinol. Metab. 94 (2009) 1353–1360.

[24] E.R. Fearon, B. Vogelstein, A genetic model for colorectal tumorigenesis, Cell61 (1990) 759–767.

[25] M. Katoh, Dysregulation of stem cell signaling network due to germlinemutation, SNP, Helicobacter pylori infection, epigenetic change and geneticalteration in gastric cancer, Cancer Biol. Ther. 6 (2007) 832–839.

[26] S.B. Baylin, P.A. Jones, A decade of exploring the cancer epigenome –biological and translational implications, Nat. Rev. Cancer 11 (2011) 726–734.

[27] X. Sagaert, C. de Wolf-Peeters, H. Noels, M. Baens, The pathogenesis of MALTlymphomas: where do we stand?, Leukemia 21 (2007) 389–396

[28] S.S. Myatt, E.W. Lam, The emerging roles of forkhead box (Fox) proteins incancer, Nat. Rev. Cancer 7 (2007) 847–859.

[29] T.B. Dansen, B.M. Burgering, Unravelling the tumor-suppressive functions ofFOXO proteins, Trends Cell Biol. 18 (2008) 421–429.

[30] L. Lin, C.T. Miller, J.I. Contreras, M.S. Prescott, S.L. Dagenais, R. Wu, J. Yee, M.B.Orringer, D.E. Misek, S.M. Hanash, T.W. Glover, D.G. Beer, The hepatocytenuclear factor 3 a gene, HNF3a (FOXA1), on chromosome band 14q13 isamplified and overexpressed in esophageal and lung adenocarcinomas,Cancer Res. 62 (2002) 5273–5279.

[31] X. Hu, H.M. Stern, L. Ge, C. O’Brien, L. Haydu, C.D. Honchell, P.M. Haverty, B.A.Peters, T.D. Wu, L.C. Amler, J. Chant, D. Stokoe, et al., Genetic alterations andoncogenic pathways associated with breast cancer subtypes, Mol. Cancer Res.7 (2009) 511–522.

[32] C. Nucera, J. Eeckhoute, S. Finn, J.S. Carroll, A.H. Ligon, C. Priolo, G. Fadda, M.Toner, O. Sheils, M. Attard, A. Pontecorvi, V. Nose, et al., FOXA1 is a potentialoncogene in anaplastic thyroid carcinoma, Clin. Cancer Res. 15 (2009) 3680–3689.

[33] C.M. Robbins, W.A. Tembe, A. Baker, S. Sinari, T.Y. Moses, S. Beckstrom-Sternberg, J. Beckstrom-Sternberg, M. Barrett, J. Long, A. Chinnaiyan, J. Lowey,E. Suh, et al., Copy number and targeted mutational analysis reveals novelsomatic events in metastatic prostate tumors, Genome Res. 21 (2011) 47–55.

[34] C.S. Grasso, Y.M. Wu, D.R. Robinson, X. Cao, S.M. Dhanasekaran, A.P. Khan, M.J.Quist, X. Jing, R.J. Lonigro, J.C. Brenner, I.A. Asangani, B. Ateeq, et al., Themutational landscape of lethal castration-resistant prostate cancer, Nature, inpress.

[35] C. Curtis, S.P. Shah, S.F. Chin, G. Turashvili, O.M. Rueda, M.J. Dunning, D.Speed, A.G. Lynch, S. Samarajiwa, Y. Yuan, S. Gräf, G. Ha, et al., The genomicand transcriptomic architecture of 2,000 breast tumours reveals novelsubgroups, Nature 486 (2012) 346–352.

[36] J. Laganière, G. Deblois, C. Lefebvre, A.R. Bataille, F. Robert, V. Giguère, Fromthe cover: location analysis of estrogen receptor a target promoters revealsthat FOXA1 defines a domain of the estrogen response, Proc. Natl. Acad. Sci.USA 102 (2005) 11651–11656.

[37] J. Schneider, M. Ruschhaupt, A. Buness, M. Asslaber, P. Regitnig, K. Zatloukal,W. Schippinger, F. Ploner, A. Poustka, H. Sültmann, Identification and meta-analysis of a small gene expression signature for the diagnosis of estrogenreceptor status in invasive ductal breast cancer, Int. J. Cancer 119 (2006)2974–2979.

[38] L. van der Heul-Nieuwenhuijsen, N.F. Dits, G. Jenster, Gene expression offorkhead transcription factors in the normal and diseased human prostate,BJU Int. 103 (2009) 1574–1580.

[39] J.R. Friedman, K.H. Kaestner, The Foxa family of transcription factors indevelopment and metabolism, Cell. Mol. Life Sci. 63 (2006) 2317–2328.

[40] L.A. Cirillo, F.R. Lin, I. Cuesta, D. Friedman, M. Jarnik, K.S. Zaret, Opening ofcompacted chromatin by early developmental transcription factors HNF3(FoxA) and GATA-4, Mol. Cell 9 (2002) 279–289.

[41] T. Sekiya, U.M. Muthurajan, K. Luger, A.V. Tulin, K.S. Zaret, Nucleosome-binding affinity as a primary determinant of the nuclear mobility of thepioneer transcription factor FoxA, Genes Dev. 23 (2009) 804–809.

[42] H. Hirai, T. Tani, N. Kikyo, Structure and functions of powerful transactivators:VP16, MyoD and FoxA, Int. J. Dev. Biol. 54 (2010) 1589–1596.

[43] A.A. Sérandour, S. Avner, F. Percevault, F. Demay, M. Bizot, C. Lucchetti-Miganeh, F. Barloy-Hubler, M. Brown, M. Lupien, R. Métivier, G. Salbert, J.Eeckhoute, Epigenetic switch involved in activation of pioneer factor FOXA1-dependent enhancers, Genome Res. 21 (2011) 555–565.

[44] K.S. Zaret, J. Watts, J. Xu, E. Wandzioch, S.T. Smale, T. Sekiya, Pioneer factors,genetic competence, and inductive signaling: programming liver andpancreas progenitors from the endoderm, Cold Spring Harb. Symp. Quant.Biol. 73 (2008) 119–126.

[45] L. Magnani, J. Eeckhoute, M. Lupien, Pioneer factors: directing transcriptionalregulators within the chromatin environment, Trends Genet. 27 (2011) 465–474.

[46] N. Gao, J. Zhang, M.A. Rao, T.C. Case, J. Mirosevich, Y. Wang, R. Jin, A. Gupta,P.S. Rennie, R.J. Matusik, The role of hepatocyte nuclear factor-3 a (ForkheadBox A1) and androgen receptor in transcriptional regulation of prostaticgenes, Mol. Endocrinol. 17 (2003) 1484–1507.

[47] C. Zhang, L. Wang, D. Wu, H. Chen, Z. Chen, J.M. Thomas-Ahner, D.L. Zynger, J.Eeckhoute, J. Yu, J. Luo, M. Brown, S.K. Clinton, et al., Definition of a FoxA1cistrome that is crucial for G1 to S-phase cell-cycle transit in castration-resistant prostate cancer, Cancer Res. 71 (2011) 6738–6748.

[48] M.A. Thorat, C. Marchio, A. Morimiya, K. Savage, H. Nakshatri, J.S. Reis-Filho, S.Badve, Forkhead box A1 expression in breast cancer is associated withluminal subtype and good prognosis, J. Clin. Pathol. 61 (2008) 327–332.

[49] B. Sahu, M. Laakso, K. Ovaska, T. Mirtti, J. Lundin, A. Rannikko, A. Sankila, J.P.Turunen, M. Lundin, J. Konsti, T. Vesterinen, S. Nordling, et al., Dual role ofFoxA1 in androgen receptor binding to chromatin, androgen signalling andprostate cancer, EMBO J. 30 (2011) 3962–3976.

[50] M.R. Green, C. Aya-Bonilla, M.K. Gandhi, R.A. Lea, J. Wellwood, P. Wood, P.Marlton, L.R. Griffiths, Integrative genomic profiling reveals conservedgenetic mechanisms for tumorigenesis in common entities of non-Hodgkin’s lymphoma, Genes Chromosom. Cancer 50 (2011) 313–326.

[51] J. Yu, H. Deshmukh, J.E. Payton, C. Dunham, B.W. Scheithauer, T. Tihan, R.A.Prayson, A. Guha, J.A. Bridge, R.E. Ferner, G.M. Lindberg, R.J. Gutmann, et al.,Array-based comparative genomic hybridization identifies CDK4 and FOXM1alterations as independent predictors of survival in malignant peripheralnerve sheath tumor, Clin. Cancer Res. 17 (2011) 1924–1934.

[52] M.T. Teh, S.T. Wong, G.W. Neill, L.R. Ghali, M.P. Philpott, A.G. Quinn, FOXM1 isa downstream target of Gli1 in basal cell carcinomas, Cancer Res. 62 (2002)4773–4780.

[53] Y. Katoh, M. Katoh, Hedgehog target genes: mechanisms of carcinogenesisinduced by aberrant hedgehog signaling activation, Curr. Mol. Med. 9 (2009)873–886.

[54] L.M. Xia, W.J. Huang, B. Wang, M. Liu, Q. Zhang, W. Yan, Q. Zhu, M. Luo, Z.Z.Zhou, D.A. Tian, Transcriptional up-regulation of FoxM1 in response tohypoxia is mediated by HIF-1, J. Cell. Biochem. 106 (2009) 247–256.

[55] T. Mizuno, H. Murakami, M. Fujii, F. Ishiguro, I. Tanaka, Y. Kondo, S. Akatsuka,S. Toyokuni, K. Yokoi, H. Osada, Y. Sekido, YAP induces malignantmesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes, Oncogene, in press.

[56] Y. Chen, B. Zheng, D.H. Robbins, D.N. Lewin, K. Mikhitarian, A. Graham, L.Rumpp, T. Glenn, W.E. Gillanders, D.J. Cole, X. Lu, B.J. Hoffman, et al., Accuratediscrimination of pancreatic ductal adenocarcinoma and chronic pancreatitisusing multimarker expression data and samples obtained by minimallyinvasive fine needle aspiration, Int. J. Cancer 120 (2007) 1511–1517.

[57] D.W. Chan, S.Y. Yu, P.M. Chiu, K.M. Yao, V.W. Liu, A.N. Cheung, H.Y. Ngan,Over-expression of FOXM1 transcription factor is associated withcervical cancer progression and pathogenesis, J. Pathol. 215 (2008)245–252.

[58] E. Gemenetzidis, A. Bose, A.M. Riaz, T. Chaplin, B.D. Young, M. Ali, D. Sugden,J.K. Thurlow, S.C. Cheong, S.H. Teo, H. Wan, A. Waseem, et al., FOXM1upregulation is an early event in human squamous cell carcinoma and it isenhanced by nicotine during malignant transformation, PLoS One 4 (2009)e4849.

[59] D.K. Yang, C.H. Son, S.K. Lee, P.J. Choi, K.E. Lee, M.S. Roh, Forkhead box M1expression in pulmonary squamous cell carcinoma: correlation withclinicopathologic features and its prognostic significance, Hum. Pathol. 40(2009) 464–470.

[60] M. Lin, L.M. Guo, H. Liu, J. Du, J. Yang, L.J. Zhang, B. Zhang, Nuclearaccumulation of glioma-associated oncogene 2 protein and enhancedexpression of forkhead-box transcription factor M1 protein in humanhepatocellular carcinoma, Histol. Histopathol. 25 (2010) 1269–1275.

[61] M. Priller, J. Pöschl, L. Abrão, A.O. von Bueren, Y.J. Cho, S. Rutkowski, H.A.Kretzschmar, U. Schüller, Expression of FoxM1 is required for theproliferation of medulloblastoma cells and indicates worse survival ofpatients, Clin. Cancer Res. 17 (2011) 6791–6801.

[62] G. Pignot, A. Vieillefond, S. Vacher, M. Zerbib, B. Debre, R. Lidereau, D.Amsellem-Ouazana, I. Bieche, Hedgehog pathway activation in humantransitional cell carcinoma of the bladder, Br. J. Cancer 106 (2012) 1177–1186.

[63] R.Y. Ma, T.H. Tong, A.M. Cheung, A.C. Tsang, W.Y. Leung, K.M. Yao, Raf/MEK/MAPK signaling stimulates the nuclear translocation and transactivatingactivity of FOXM1c, J. Cell Sci. 118 (2005) 795–806.

M. Katoh et al. / Cancer Letters 328 (2013) 198–206 205

[64] I.C. Wang, Y.J. Chen, D. Hughes, V. Petrovic, M.L. Major, H.J. Park, Y. Tan, T.Ackerson, R.H. Costa, Forkhead box M1 regulates the transcriptional networkof genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase, Mol. Cell. Biol. 25 (2005) 10875–10894.

[65] A. Ahmad, Z. Wang, D. Kong, S. Ali, Y. Li, S. Banerjee, R. Ali, F.H. Sarkar, FoxM1down-regulation leads to inhibition of proliferation, migration and invasionof breast cancer cells through the modulation of extra-cellular matrixdegrading factors, Breast Cancer Res. Treat. 122 (2010) 337–346.

[66] Z. Wang, A. Ahmad, Y. Li, S. Banerjee, D. Kong, F.H. Sarkar, Forkhead box M1transcription factor: a novel target for cancer therapy, Cancer Treat. Rev. 36(2010) 151–156.

[67] K.M. Huynh, J.W. Soh, R. Dash, D. Sarkar, P.B. Fisher, D. Kang, FOXM1expression mediates growth suppression during terminal differentiation ofHO-1 human metastatic melanoma cells, J. Cell. Physiol. 226 (2011) 194–204.

[68] B. Bao, Z. Wang, S. Ali, D. Kong, S. Banerjee, A. Ahmad, Y. Li, A.S. Azmi, L. Miele,F.H. Sarkar, Over-expression of FoxM1 leads to epithelial–mesenchymaltransition and cancer stem cell phenotype in pancreatic cancer cells, J. Cell.Biochem. 112 (2011) 2296–2306.

[69] D. Frescas, M. Pagano, Deregulated proteolysis by the F-box proteins SKP2and b-TrCP: tipping the scales of cancer, Nat. Rev. Cancer 8 (2008) 438–449.

[70] J.T. Xia, H. Wang, L.J. Liang, B.G. Peng, Z.F. Wu, L.Z. Chen, L. Xue, Z. Li, W. Li,Overexpression of FOXM1 is associated with poor prognosis andclinicopathologic stage of pancreatic ductal adenocarcinoma, Pancreas 41(2012) 629–635.

[71] S. Reagan-Shaw, N. Ahmad, The role of Forkhead-box Class O (FoxO)transcription factors in cancer: a target for the management of cancer,Toxicol. Appl. Pharmacol. 224 (2007) 360–368.

[72] X.Y. Dong, C. Chen, X. Sun, P. Guo, R.L. Vessella, R.X. Wang, L.W. Chung, W.Zhou, J.T. Dong, FOXO1A is a candidate for the 13q14 tumor suppressor geneinhibiting androgen receptor signaling in prostate cancer, Cancer Res. 66(2006) 6998–7006.

[73] L. Yang, H.M. Hu, A. Zielinska-Kwiatkowska, H.A. Chansky, FOXO1 is a directtarget of EWS-Fli1 oncogenic fusion protein in Ewing’s sarcoma cells,Biochem. Biophys. Res. Commun. 402 (2010) 129–134.

[74] X. Liu, Z. Zhang, L. Sun, N. Chai, S. Tang, J. Jin, H. Hu, Y. Nie, X. Wang, K. Wu,et al., MicroRNA-499-5p promotes cellular invasion and tumor metastasis incolorectal cancer by targeting FOXO4 and PDCD4, Carcinogenesis 32 (2011)1798–1805.

[75] P.O. Hasselgren, Ubiquitination, phosphorylation, and acetylation – triplethreat in muscle wasting, J. Cell. Physiol. 213 (2007) 679–689.

[76] J.Y. Yang, M.C. Hung, A new fork for clinical application: targeting forkheadtranscription factors in cancer, Clin. Cancer Res. 15 (2009) 752–757.

[77] R. Lüpertz, Y. Chovolou, K. Unfried, A. Kampkötter, W. Wätjen, R. Kahl, Theforkhead transcription factor FOXO4 sensitizes cancer cells to doxorubicin-mediated cytotoxicity, Carcinogenesis 29 (2008) 2045–2052.

[78] A. Polter, S. Yang, A.A. Zmijewska, T. van Groen, J.H. Paik, R.A. Depinho, S.L.Peng, R.S. Jope, X. Li, Forkhead box, class O transcription factors in brain:regulation and behavioral manifestation, Biol. Psychiatry 65 (2009) 150–159.

[79] A.A. Szypowska, H. de Ruiter, L.A. Meijer, L.M. Smits, B.M. Burgering,Oxidative stress-dependent regulation of Forkhead box O4 activity bynemo-like kinase, Antioxid. Redox Signal. 14 (2011) 563–578.

[80] W. Fu, Q. Ma, L. Chen, P. Li, M. Zhang, S. Ramamoorthy, Z. Nawaz, T.Shimojima, H. Wang, Y. Yang, Z. Shen, Y. Zhang, et al., MDM2 actsdownstream of p53 as an E3 ligase to promote FOXO ubiquitination anddegradation, J. Biol. Chem. 284 (2009) 13987–14000.

[81] A. Oteiza, N. Mechti, The human T-cell leukemia virus type 1 oncoprotein taxcontrols forkhead box O4 activity through degradation by the proteasome, J.Virol. 85 (2011) 6480–6491.

[82] J. Momand, D. Jung, S. Wilczynski, J. Niland, The MDM2 gene amplificationdatabase, Nucleic Acids Res. 26 (1998) 3453–3459.

[83] B. Streubel, U. Vinatzer, A. Lamprecht, M. Raderer, A. Chott,T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrentchromosomal aberration in MALT lymphoma, Leukemia 19 (2005) 652–658.

[84] C.G. Mullighan, S. Goorha, I. Radtke, C.B. Miller, E. Coustan-Smith, J.D. Dalton,K. Girtman, S. Mathew, J. Ma, S.B. Pounds, X. Su, C.H. Pui, et al., Genome-wideanalysis of genetic alterations in acute lymphoblastic leukaemia, Nature 446(2007) 758–764.

[85] T. Ernst, J. Score, M. Deininger, C. Hidalgo-Curtis, P. Lackie, W.B. Ershler, J.M.Goldman, N.C. Cross, F. Grand, Identification of FOXP1 and SNX2 as novel ABL1fusion partners in acute lymphoblastic leukaemia, Br. J. Haematol. 153 (2011)43–46.

[86] K.G. Hermans, H.A. van der Korput, R. van Marion, D.J. van de Wijngaart, A.Ziel-van der Made, N.F. Dits, J.L. Boormans, T.H. van der Kwast, H. van Dekken,C.H. Bangma, H. Korsten, R. Kraaij, et al., Truncated ETV1, fused to noveltissue-specific genes, and full-length ETV1 in prostate cancer, Cancer Res. 68(2008) 7541–7549.

[87] A. Goatly, C.M. Bacon, S. Nakamura, H. Ye, I. Kim, P.J. Brown, A. Ruskoné-Fourmestraux, P. Cervera, B. Streubel, A.H. Banham, M.Q. Du, FOXP1abnormalities in lymphoma: translocation breakpoint mapping revealsinsights into deregulated transcriptional control, Mod. Pathol. 21 (2008)902–911.

[88] T. Klampfl, A. Harutyunyan, T. Berg, B. Gisslinger, M. Schalling, K. Bagienski, D.Olcaydu, F. Passamonti, E. Rumi, D. Pietra, R. Jäger, L. Pieri, et al., Genomeintegrity of myeloproliferative neoplasms in chronic phase and duringdisease progression, Blood 118 (2011) 167–176.

[89] M.I. Toma, M. Grosser, A. Herr, D.E. Aust, A. Meye, C. Hoefling, S. Fuessel, D.Wuttig, M.P. Wirth, G.B. Baretton, Loss of heterozygosity and copy numberabnormality in clear cell renal cell carcinoma discovered by high-densityaffymetrix 10K single nucleotide polymorphism mapping array, Neoplasia 10(2008) 634–642.

[90] A.H. Banham, N. Beasley, E. Campo, P.L. Fernandez, C. Fidler, K. Gatter, M.Jones, D.Y. Mason, J.E. Prime, P. Trougouboff, K. Wood, J.L. Cordell, The FOXP1winged helix transcription factor is a novel candidate tumor suppressor geneon chromosome 3p, Cancer Res. 61 (2001) 8820–8829.

[91] M.H. Yang, B.R. Lin, C.H. Chang, S.T. Chen, S.K. Lin, M.Y. Kuo, Y.M. Jeng, M.L.Kuo, C.C. Chang, Connective tissue growth factor modulates oral squamouscell carcinoma invasion by activating a miR-504/FOXP1 signalling, Oncogene31 (2012) 2401–2411.

[92] V.J. Craig, S.B. Cogliatti, J. Imig, C. Renner, S. Neuenschwander, H. Rehrauer, R.Schlapbach, S. Dirnhofer, A. Tzankov, A. Müller, Myc-mediated repression ofmicroRNA-34a promotes high-grade transformation of B-cell lymphoma bydysregulation of FoxP1, Blood 117 (2011) 6227–6236.

[93] J. Datta, H. Kutay, M.W. Nasser, G.J. Nuovo, B. Wang, S. Majumder, C.G. Liu, S.Volinia, C.M. Croce, T.D. Schmittgen, K. Ghoshal, S.T. Jacob, Methylationmediated silencing of MicroRNA-1 gene and its role in hepatocellularcarcinogenesis, Cancer Res. 68 (2008) 5049–5058.

[94] Y. Zhang, S. Li, L. Yuan, Y. Tian, J. Weidenfeld, J. Yang, F. Liu, A.L. Chokas, E.E.Morrisey, Foxp1 coordinates cardiomyocyte proliferation through both cell-autonomous and nonautonomous mechanisms, Genes Dev. 24 (2010) 1746–1757.

[95] H. Hu, B. Wang, M. Borde, J. Nardone, S. Maika, L. Allred, P.W. Tucker, A. Rao,Foxp1 is an essential transcriptional regulator of B cell development, Nat.Immunol. 7 (2006) 819–826.

[96] H.B. Koon, G.C. Ippolito, A.H. Banham, P.W. Tucker, FOXP1: a potentialtherapeutic target in cancer, Expert Opin Ther. Targets 11 (2007) 955–965.

[97] S.L. Barrans, J.A. Fenton, A. Banham, R.G. Owen, A.S. Jack, Strong expression ofFOXP1 identifies a distinct subset of diffuse large B-cell lymphoma (DLBCL)patients with poor outcome, Blood 104 (2004) 2933–2935.

[98] S.L. Han, X.L. Wu, L. Wan, Q.Q. Zeng, J.L. Li, Z. Liu, FOXP1 expression predictspolymorphic histology and poor prognosis in gastric mucosa-associatedlymphoid tissue lymphomas, Dig. Surg. 26 (2009) 156–162.

[99] Y. Zhang, S. Zhang, X. Wang, J. Liu, L. Yang, S. He, L. Chen, J. Huang, Prognosticsignificance of FOXP1 as an oncogene in hepatocellular carcinoma, J. Clin.Pathol. 65 (2012) 528–533.

[100] S.B. Fox, P. Brown, C. Han, S. Ashe, R.D. Leek, A.L. Harris, A.H. Banham,Expression of the forkhead transcription factor FOXP1 is associated withestrogen receptor a and improved survival in primary human breastcarcinomas, Clin. Cancer Res. 10 (2004) 3521–3527.

[101] M. Katoh, M. Katoh, Identification and characterization of human FOXN5 andrat Foxn5 genes in silico, Int. J. Oncol. 24 (2004) 1339–1344.

[102] E.E. Santo, M.E. Ebus, J. Koster, J.H. Schulte, A. Lakeman, P. van Sluis, J.Vermeulen, D. Gisselsson, I. Øra, S. Lindner, P.G. Buckley, R.L. Stallings, et al.,Oncogenic activation of FOXR1 by 11q23 intrachromosomal deletion–fusionsin neuroblastoma, Oncogene 31 (2012) 1571–1581.

[103] S.A. Mani, J. Yang, M. Brooks, G. Schwaninger, A. Zhou, N. Miura, J.L. Kutok, K.Hartwell, A.L. Richardson, R.A. Weinberg, Mesenchyme Forkhead 1 (FOXC2)plays a key role in metastasis and is associated with aggressive basal-likebreast cancers, Proc. Natl. Acad. Sci. USA 104 (2007) 10069–10074.

[104] Y. Xue, R. Cao, D. Nilsson, S. Chen, R. Westergren, E.M. Hedlund, C. Martijn, L.Rondahl, P. Krauli, E. Walum, S. Enerbäck, Y. Cao, FOXC2 controls Ang-2expression and modulates angiogenesis, vascular patterning, remodeling, andfunctions in adipose tissue, Proc. Natl. Acad. Sci. USA 105 (2008) 10167–10172.

[105] Y. Li, W. Yang, Q. Yang, S. Zhou, Nuclear localization of GLI1 and elevatedexpression of FOXC2 in breast cancer is associated with the basal-likephenotype, Histol. Histopathol. 27 (2012) 475–484.

[106] N. Nishida, K. Mimori, T. Yokobori, T. Sudo, F. Tanaka, K. Shibata, H. Ishii, Y.Doki, M. Mori, FOXC2 is a novel prognostic factor in human esophagealsquamous cell carcinoma, Ann. Surg. Oncol. 18 (2011) 535–542.

[107] I. Cuesta, K.S. Zaret, P. Santisteban, The forkhead factor FoxE1 binds to thethyroperoxidase promoter during thyroid cell differentiation and modifiescompacted chromatin structure, Mol. Cell. Biol. 27 (2007) 7302–7314.

[108] I. Landa, S. Ruiz-Llorente, C. Montero-Conde, L. Inglada-Pérez, F. Schiavi, S.Leskelä, G. Pita, R. Milne, J. Maravall, I. Ramos, V. Andía, P. Rodríguez-Poyo,et al., The variant rs1867277 in FOXE1 gene confers thyroid cancersusceptibility through the recruitment of USF1/USF2 transcription factors,PLoS Genet. 5 (2009) e1000637.

[109] I. Venza, M. Visalli, B. Tripodo, G. de Grazia, S. Loddo, D. Teti, M. Venza, FOXE1is a target for aberrant methylation in cutaneous squamous cell carcinoma,Br. J. Dermatol. 162 (2010) 1093–1097.

[110] A. Brancaccio, A. Minichiello, M. Grachtchouk, D. Antonini, H. Sheng, R.Parlato, N. Dathan, A.A. Dlugosz, C. Missero, Requirement of the forkheadgene Foxe1, a target of sonic hedgehog signaling, in hair folliclemorphogenesis, Hum. Mol. Genet. 13 (2004) 2595–2606.

[111] J.E. Watson, N.A. Doggett, D.G. Albertson, A. Andaya, A. Chinnaiyan, H. vanDekken, D. Ginzinger, C. Haqq, K. James, S. Kamkar, D. Kowbel, D. Pinkel, et al.,Integration of high-resolution array comparative genomic hybridizationanalysis of chromosome 16q with expression array data refines commonregions of loss at 16q23-qter and identifies underlying candidate tumorsuppressor genes in prostate cancer, Oncogene 23 (2004) 3487–3494.

206 M. Katoh et al. / Cancer Letters 328 (2013) 198–206

[112] P.K. Lo, J.S. Lee, X. Liang, L. Han, T. Mori, M.J. Fackler, H. Sadik, P. Argani, T.K.Pandita, S. Sukumar, Epigenetic inactivation of the potential tumorsuppressor gene FOXF1 in breast cancer, Cancer Res. 70 (2010)6047–6058.

[113] P.K. Lo, J.S. Lee, S. Sukumar, The p53–p21WAF1 checkpoint pathway plays aprotective role in preventing DNA rereplication induced by abrogation ofFOXF1 function, Cell. Signal. 24 (2012) 316–324.

[114] J. Nilsson, K. Helou, A. Kovács, P.O. Bendahl, G. Bjursell, M. Fernö, P. Carlsson,M. Kannius-Janson, Nuclear Janus-activated kinase 2/nuclear factor 1–C2suppresses tumorigenesis and epithelial-to-mesenchymal transition byrepressing Forkhead box F1, Cancer Res. 70 (2010) 2020–2029.

[115] A. Feuerborn, P.K. Srivastava, S. Küffer, W.A. Grandy, T.P. Sijmonsma, N. Gretz,B. Brors, H.J. Gröne, The Forkhead factor FoxQ1 influences epithelialdifferentiation, J. Cell. Physiol. 226 (2011) 710–719.

[116] H. Zhang, F. Meng, G. Liu, B. Zhang, J. Zhu, F. Wu, S.P. Ethier, F. Miller, G. Wu,Forkhead transcription factor FOXQ1 promotes epithelial–mesenchymaltransition and breast cancer metastasis, Cancer Res. 71 (2011) 1292–1301.

[117] Y. Qiao, X. Jiang, S.T. Lee, R.K. Karuturi, S.C. Hooi, Q. Yu, FOXQ1 regulatesepithelial–mesenchymal transition in human cancers, Cancer Res. 71 (2011)3076–3086.

[118] D.J. Birnbaum, J. Adélaïde, E. Mamessier, P. Finetti, A. Lagarde, G. Monges, F.Viret, A. Gonçalvès, O. Turrini, J.R. Delpero, J. Iovanna, M. Giovannini, et al.,Genome profiling of pancreatic adenocarcinoma, Genes Chromosom. Cancer50 (2011) 456–465.

[119] A.M. Adesina, Y. Nguyen, P. Guanaratne, J. Pulliam, D. Lopez-Terrada, J.Margolin, M. Finegold, FOXG1 is overexpressed in hepatoblastoma, Hum.Pathol. 38 (2007) 400–409.

[120] S.P. Shah, M. Köbel, J. Senz, R.D. Morin, B.A. Clarke, K.C. Wiegand, G. Leung, A.Zayed, E. Mehl, S.E. Kalloger, M. Sun, R. Giuliany, et al., Mutation of FOXL2

in granulosa-cell tumors of the ovary, N. Engl. J. Med. 360 (2009)2719–2729.

[121] T. Zuo, L. Wang, C. Morrison, X. Chang, H. Zhang, W. Li, Y. Liu, Y. Wang, X. Liu,M.W. Chan, J.Q. Liu, R. Love, et al., FOXP3 is an X-linked breast cancersuppressor gene and an important repressor of the HER-2/ErbB2 oncogene,Cell 129 (2007) 1275–1286.

[122] L. Wang, R. Liu, W. Li, C. Chen, H. Katoh, G.Y. Chen, B. McNally, L. Lin, P. Zhou,T. Zuo, K.A. Cooney, Y. Liu, et al., Somatic single hits inactivate the X-linkedtumor suppressor FOXP3 in the prostate, Cancer Cell 16 (2009) 336–346.

[123] Z. Li, G. Tuteja, J. Schug, K.H. Kaestner, Foxa1 and Foxa2 are essential forsexual dimorphism in liver cancer, Cell 148 (2012) 72–83.

[124] F. Westermann, M. Schwab, Genetic parameters of neuroblastomas, CancerLett. 184 (2002) 127–147.

[125] M. Eilers, R.N. Eisenman, Myc’s broad reach, Genes Dev. 22 (2008) 2755–2766.

[126] A.J. Levine, M. Oren, The first 30 years of p53: growing ever more complex,Nat. Rev. Cancer 9 (2009) 749–758.

[127] D.L. Burkhart, J. Sage, Cellular mechanisms of tumour suppression by theretinoblastoma gene, Nat. Rev. Cancer 8 (2008) 671–682.

[128] S.K. Radhakrishnan, U.G. Bhat, D.E. Hughes, I.C. Wang, R.H. Costa, A.L. Gartel,Identification of a chemical inhibitor of the oncogenic transcription factorforkhead box M1, Cancer Res. 66 (2006) 9731–9735.

[129] M. Wang, A.L. Gartel, Micelle-encapsulated thiostrepton as an effectivenanomedicine for inhibiting tumor growth and for suppressing FOXM1 inhuman xenografts, Mol. Cancer Ther. 10 (2011) 2287–2297.

[130] S. Koren, M.C. Schatz, B.P. Walenz, J. Martin, J.T. Howard, G. Ganapathy, Z.Wang, D.A. Rasko, W.R. McCombie, E.D. Jarvis, A.M. Phillippy, Hybrid errorcorrection and de novo assembly of single-molecule sequencing reads, Nat.Biotechnol. 30 (2012) 693–700.

本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。

学霸图书馆（www.xuebalib.com）是一个“整合众多图书馆数据库资源，

提供一站式文献检索和下载服务”的24 小时在线不限IP

图书馆。

图书馆致力于便利、促进学习与科研，提供最强文献下载服务。

图书馆导航：

图书馆首页 文献云下载 图书馆入口 外文数据库大全 疑难文献辅助工具